Manufacture of ketotetrahydro



Patented Jan. 3, 1 950 MANUFACTURE OF KETOTETRAHYDRO- PYRIDINE DERIVATIVES AND HYDROXY- PYRIDINE DERIVATIVES Franz Bergel and Aaron Cohen, Welwyn Garden City, England, assignors, by mesne assignments, to Hoffmann-La Roche Inc., Nutley, N. J., a corporation of New Jersey No Drawing. Original application April 8, 1943,

Serial No. 482,324.

Divided and this application August 23, 1944, Serial No. 550,855.

Eire and Great Britain March 9, 1942 Section 1, Public Law 690, August 8, 1946 Patent expires March 9, 1962 3 Claims.

This invention relates to the synthesis of N- substituted pyridinium salts containinga 3-hydroxyl group, and of 3-hydroxypyridine derivatives related to vitamin Be and intermediates therefor.

ooox 011,000): I' oooz ooooY o o.oooY R- H -R A I N -Z'OH R, 3N OR" it I I R II According to the invention, of our oo-pending application Serial No. 482,324, now Patent 2,440,- 218 issued April 20, 1948, of which this application is divisional, compounds of the general Formula I are cyclised to yield ketotetrahydropyridine derivatives of the general Formula II. In Formula I R may be an alkyl group or such other group as may be attached to the a-carbon atom of an u-amino-acid without interfering with the reactions taking place in the process according to the present invention; R is an alkyl or aralkyl group; R" is hydrogen, and X, Y and Z, which are not necessarily identical, are lower alkyl groups such as methyl or ethyl. Compounds of Formula I are obtained, for example, by the reaction between an ester of an a-aminoacid and a mono-acylsuccinic ester according to the process described in specification of United States application Serial No. 455,383, filed August 19, 1942, now Patent No. 2,384,068. Thus, a starting material made from the ethyl ester of N-methylalaninc and diethyl e-formyl-succinate according to the aforesaid specification would have Formula I where R=R=CH3; R"=I-I, and X=Y=Z:C2I-I5.

The above mentioned cyclisation is carried out according to the invention ofthe aforesaid co pending application Serial No. 482,324 by submitting compounds of Formula I to the action of an alkali metal such as sodium, or alcoholates thereof, preferably in an inert solvent such as benzene or toluene and under an inert atmosphere such as nitrogen. The reaction proceeds with the elimination of the elements of the alcohol represented by Z.OH, and with the formation of the alkali metal derivative of the ketotetrahydropyridine derivative, which has the Formula II, in which R, R, R", X and Y bear the same interpretation as given above. The alkali metal derivative is suitably treated with acid to liberate the Compound II, and the latter is converted into a hydrohalide salt by treatment with anhydrous hydrogen halide. These salts are expressed by the Formula III, showing the enolic form, and constituting a substituted 3-hydroxydihydropyridine hydro chloride, corresponding to a substituted 3- ketotetrahydropyridine hydrochloride.

According to the process of our co-pending ap-- .plication Serial No. 550,856, now Patent 2,440,219, issued April 20, 1948, which is also a divisional of application Serial No. 482,324 salts such as the hydrochloride shown in Formula III are submitted 'to a dehydrogenation, which has been discovered to occur, for instance, by exposing the salt in absolute alcohol and ether to an oxygen-containi'ng gas such as air or to oxygen. With the loss of two hydrogen atoms, a B-hydroxypyridinium chloride is formed, having the Formula IV.

According to the present invention it been found that in the case where the quaternary pyridinium salt IV has R benzyl, it is possible to effect its conversion into a pyridine derivative by treating the salt with hydrogen in the presence of a hydrogenation catalyst such as palladised charcoal, whereby the benzyl group is eliminated and replaced by hydrogen with the formation of the hydrochloride of a 3-hydroxypyridine deriva tive illustrated by the Formula V. Thus, for ex-- ample, by suitable choice of starting material within the scope of the definitions given for Formula I, it has been discovered that Z-methyl- 3-hydroxy-4; -dicarbmethoxypyridine and the corresponding free acid 2-methyl-3-hydroxy-4; 5-dicarboxypyridine can be synthesised. If the pyridinium salts of Formula IV are treated with one equivalent of cold alkali, the corresponding phenol betaine is formed via the quaternary base, and if excess of alkali is used and the solution is heated, hydrolysis of the ester groups COOX and COOY occurs and a betaine of the corresponding hydroxy-dicarboxylic acid is formed.

The pyridinium salts and the pyridine derivatives described are useful intermediates in the synthesis of vitamin B6.

The following examples illustrate how the process of the invention may be carried into effect:

1. A solution of 30 parts by weight of the condensation product obtained from the ethyl ester of N-methyl alanine and diethyl -formyl-succinate (as described in Example 7 of specification of application Serial No. 455,383), in 120 parts by volume of dry benzene is added to a benzene su's pension of 2.1 parts by weight of powdered-sodium in an atmosphere of dry nitrogen, and the mixture is gently heated under reflux. The sodium dissolves, and heating is. then continued for, 1 hour. The solution is cooled and shaken with a mixture of ice and the calculated amount of acetic acid containing a small amount of sulphuric acid which is equivalent to the sodium used. The benzene extract is washed with water, sodium bicarbonate solution, water again, dried and freed from solvent. The residual oilis dissolved in concentrated anhydrous alcoholic hydrogen chloride and treated with excess of dry ether. The prode gradually added to precipitate the product. By

repetition of the process, the product, 1:2-dimethyl 3-hydroxy-4:5-dicarbethoxypyridinium chloride (IV, where R=R=CH3, R=H, and X=Y=C2H5) crystallises out 7 in colourless needles, having a melting point of 165 C. with decomposition.

The quaternary base corresponding to this pyridinium salt gives riseto a phenolic betaine, and, by hydrolysis of the ester groups, to a betaine of the hydroxydicarboxylic acid as follows: A solution of 6.1 parts by weight of 1:2-dimethyl- 3-hydroxy 4:5 dicarbethoxy-pyridinium chloride in parts by volume of water is treated at 0 C. with one molecular equivalent of 2 normal sodium hydroxide solution. A mass of fine needles soon crystallises out. This is filtered off and recrystallised from a concentrated aqueous solution. So obtained,'it melts between 85 and 100C, but when dried in vacuo it loses water and yields 3.8 parts by weight of a pale yellow substance which, when anhydrous, crystallises from ethyl acetate in pale yellow prisms having a melting point of 162-165 C. This compound is the phenolic betaine of 1:2-dimethyl-3-hydroxy- 4: 5-dicarbethoxypyridinium hydroxide.

A solution of 6.1 parts by weight of 1:2-dimethyl 3 hydroxy-4:5-dicarbethoxypyridinium chloride in 20 parts of water is gently warmed with a concentrated aqueous solution of 2.4 parts by weight of sodium hydroxide for 30 minutes.

The solution is made just acid to litmus by adding acetic acid. The product which separates crystallises from water in colourless leaflets having a melting point of 230 C. with decomposition. It is a betaine of 1:2-dimethyl-3 hydroxy-4:5-dicarboxypyridinium hydroxide.

2. dl-Alanine methyl ester is mixed with slightly more than the molecular equivalent of benzaldehyde. The Schiff base formed is dried in ethereal solution, the ether removed, and the residue dissolved in approximately four parts by volume of methyl alcohol and hydrogenated over palladised charcoal. After removal of the catalyst and solvent, the residue is distilled, yielding the methyl ester of N ben'zyl alanine (methyl a-benzylaminopropionate) as a colourless liquid having a boiling point of 131-133 C./10 mm. 19.3 parts by weight of this compound are mixed with 17.5 parts by weight of dimethyl a-formylsuccinate in accordance with the method described in specification of application Serial No.

' 455,383. After heating the mixture for 1 hour on 'is washed with cold sodium bicarbonate soluthe water-bath, it is cooled and dissolved in dry ether or benzene. A small amount of diketopiperazine derivative corresponding to the amino ester, separates and is collected. The solution tion, dried, freed from solvent and the residue distilled, yielding the condensation product (I;

where as a viscous yellow oil having a boiling point of about 200 C. 0.3 mm. r

A solution of 36 parts by weight of this compound in 120 parts by volume of dry benzene, in which are suspended 2.4 parts by weight of powdered sodium, is boiled underrefiux in anatmosphere of nitrogen. Dissolution of the sodium is facilitated by the addition of a small amount of sodium methoxide or sodium ethoxide. Heat'- ing is then continued for 1 hour and the solution is then cooled and acidified as described in Example 1. The washed and dried benzen'e'extract is freed from solvent and treated with sufilcient anhydrous alcoholic'hydrogen chloride to form the hydrochloride of the cyclisation product. This is precipitated as a slowly solidifying oily product by the addition of excess of anhydrous ether. However, by adding insufiicient ether for the precipitation to occur and by'exposing the alcoholic-ethereal solution to air or oxygen for at least one day, the dehydrogenation product separates gradually as fine colourless needles having a melting point of 146-148 C. This compound is 1 benzyl-2-methyl-3-hydroxy 4:5 -dicarbmethoxy pyridinium chloride (IV, where R=CH3, R=CH2Ph, R"=H, X=Y=CH 3). This quaternary salt yields the corresponding phenolic betaine as follows: A cold concentrated aqueous solution of '7 parts by weight of 1 benzyl- 2 methyl 3 hydroxy 4:5 dicarbmethoxypyridinium chloride is treated with one molecular equivalent of cold 2 N sodium hydroxide. The product soon crystallises out and is filtered'off and washed with a little water and dried in vacuo,

being obtained in a yieldof slightly more than 6 parts by weight. It crystallises from water in fiat needles which contain some water of crystallisation and melt partly about C, The anhydrous .material becomes yellow on heating and melts to reddish liquid at '138-140C. It is the phenolic betaine of l-benizyl-Z-methyl-B-hydroxy-4 5-dicarbmethoxypridinium hydroxide.

A solution of 6.5 parts by weight of l-benzyl- 2 methyl 3 hydroxy 4:5 dicarbmethoxypridinium chloride in 20 parts by volume of methyl alcohol is shaken with hydrogen in the presence of 0.5 part by weight of palladised charcoal (1:4). The calculated amount of hydrogen is taken up in a few minutes and after filtering from the catalyst and evaporating off the methyl alcohol under reduced pressure, the product (4.2 parts by weight) is crystallised from alcoholether in colourless needles having a melting point of 165 0., followed by decomposition. It is obvious that the same product is obtained by carrying out the hydrogenation on the above phenolic betaine in a methyl alcoholic solution containing one molecular equivalent of hydrogen chloride.

This product is 2-methyl-3-hydroxy-4:5-dicarbmethoxypyridine hydrochloride (V, Where R=X=Y=CH3 and R"=H). It gives a blue colour with the Gibbs phenol reagent.

It is hydrolysed by heating on the water-bath with 3 molecular equivalents of 6 normal sodium hydroxide. The solution is made slightly acid to litmus with 5 to 6 normal hydrochloric acid, and the product 2-methyl-3-hydroxy-4:S-dicarboxypyridine, crystallises out having a melting point of 259 C. with decomposition, agreeing in properties with the same substance synthesised by another method of Ichiba and Emoto (Sci. Papers, Inst. Phys. Chem. Res., Tokyo, 1941, 38, 347). On further crystallisation the melting point is raised to 265 C.

3. The preparation in accordance with Example 2 is repeated but with the substitution of 5.6 parts of sodium methoxide in place of 2.4 parts of powdered sodium. The reactions and quantities are otherwise identical with those of Example 2 and the same product is obtained.

We claim:

1. A process for the manufacture of compounds selected from the group consisting of those having the general formulae which comprises hydrogenating, in the presence of a hydrogenation catalyst, a compound of the eneral formula C 0 0 lower alkyl 0.0 0 0 lower alkyl ooox HO.C 0.000Y

and

which comprises hydrogenating, in the presence of palladized charcoal, a compound of the general formula ('30 0 lower alkyl 110.0 0.0 O 0 lower alkyl Benzyl in which R is alkyl, R." is hydrogen, X and Y are members selected from the group consisting of hydrogen and lower alkyl radicals, and A is an anion.

3. A process for the manufacture of the compound having the formula OOOH H0.0 C.C OOH OHa.C CH

which comprises hydrogenating, in the presence of palladized charcoal, the compound 1-benzy1-2- methyl-3-hydroxy-4 S-dicarbmethoxy pyridinium chloride, of the formula 10003, HO.C/ 0.000011,

enzyl and subjecting the hydrogenated product, of formula 110.0 CLCOOCH;

CH. CH

to hydrolysis in an alkaline medium, and thereafter acidifying the reaction mixture.

FRANZ BERGEL. AARON COHEN.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS OTHER REFERENCES Berichte, 723, Feb. 9, 1939, pp. 305-311.

Ichiba, Scientific Paper of Inst. of Phys. and Chemical Research, pp. 347-352, May 1941.

Chem. Abstracts, Oct. 10, 1947; p. 6248. 

1. A PROCESS FOR THE MANUFACTURE OF COMPOUNDS SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THE GENERAL FORMULAE 